Human papillomaviruses (HPVs) are the causative agent of almost all cervical cancers, and are associated with nearly one-third of oral cancers. While relatively few infections develop into cancer, persistent infections lasting more than 10 years greatly increase the risk of developing cancer. The lack of effective treatments for existing infections poses a formidable challenge to the eradication of HPV-associated cancers. The development of treatments has been hindered in part by the complex life cycle of the virus. HPVs infect and replicate in the stratified epithelium. Each stage of the viral life cycle is coordinated with the program of cellular differentiation within the epidermis. Although considerable research has elucidated how individual viral proteins promote carcinogenesis, little is known about how HPV regulates cellular targets at different stages of cellular differentiation, and how such regulation can in turn affect the life cycle. We have previously shown that the DEK is an induced target of the HPV16 E7 oncogene and inhibits cell death and senescence. We have recently found that HPV16 induced the expression of DEK in differentiated cells. In addition, DEK overexpression in an organotypic epithelial raft model system was sufficient for delayed expression of differentiation markers, mimicking the effects of HPV infection. Finally, we have found that further increasing DEK levels in HPV positive cells stimulated the viral life cycle. Based on these findings, we hypothesize that HPV upregulates DEK in differentiated cells in order to stimulate the viral life cycle. In Specific Aim 1 we will identify which stage of the viral life cycle is stimulated by DEK. In Specific Aim 2 we will determine if DEK is required for completion of the viral life cycle and begin to dissect the mechanism through which it exerts its function. In Specific Aim 3 we will examine global changes in gene expression to identify the cellular pathways that are regulated by DEK during HPV16 infection. PUBLIC HEALTH RELEVANCE: While recently introduced vaccines can prevent infection by HPV there are currently few treatment options for existing HPV infections. The goal of this research is to identify genes and processes that are critical for the virus and potentially could be used as the basis to design new drugs to treat HPV infection.